Clinical Trials of Obese Patients Lacking

There are huge numbers of markedly obese patients in the US. While I have seen little literature on this topic, I am acutely aware of in my own practice is the lack of data on treating the morbidly obese.
For example, a weight >300 pounds is a common exclusion on many clinical trials. The result is that there is little evidence-based medicine, and considerable problem knowing how to dose patients with a variety of medications. Little pharmacokinetic or pharmacodynamic information is available, and much of that is limited to healthy volunteers. Accurate physical examination is near impossible at times. Many patients are too obese to have diagnostic imaging studies, especially CAT scans or MRI scans, reducing us, it seems, to veterinary medicine. There are various recipes for drug dosing in obese patients—some based on ideal body weight (IBW), some on actual body weight, or some based on witchcraft (somewhere in the middle between IBW plus a percentage of the excess weight). The concern about the lack of evidence is particularly timely now, given that serious illness and deaths from Influenza A H1N1 are disproportionately affecting the obese. Some studies are proposed, as Oseltamivir Pharmacokinetics in Morbid Obesity (OPTIMO), but are just getting started (November 2009). Given the unfortunate change in patient demographics in the US and the epidemic of obesity here, clinical trials focusing on this population would be timely and most welcome.

Hurricane Katrina Revisited...and Likely Consequences

If it is hurricane season, you can count on someone dredging up the story of Dr. Anna Pou and her nurse colleagues, who had been been accused of homicide for the deaths of some patients under their care during Hurricane Katrina. The New Orleans D.A. asked a grand jury to indict them; the grand jury declined. This year's second guessing begins with a disappointing ProPublica/New York Times joint exposé that really adds nothing enlightening to the debate and neglects important considerations.

In the aftermath of Katrina, these devoted healthcare workers stayed to care for their patients as best they could, despite searing temperatures and extreme humidity, lack of supplies, exhaustion, and considerable risk to themselves. As part of their care, they prioritized allocating their limited resources. “Triage” --this process of allocation-- is a long-standing practice in medical care, and will be more visible when we are faced with the next disaster or epidemic. The concept of triage, which has it's roots in battlefield medicine, in it's simplest form involves sorting patients into three groups – those who are likely to survive with no medical care, those that are unlikely to survive given the level of care available at the site, and those that likely will survive if treated at the site. The limited care that is available is then provided first to the group that is deemed most likely to benefit from it, and only when that group has been treated, is it provided to the others. Dr. Pou and her colleagues were faced with a situation that was, in many ways, similar to a battlefield situation, in that their resources were extremely limited, to the point where they couldn't save everyone. Thus it seems that the most sensible thing for them to have done was to focus their efforts on those who were likely to survive, and do whatever they could to make those who were unlikely to survive as comfortable as possible in their remaining hours.

There are unintended consequences of the homicide accusations that were not addressed by this article. For example, many patients currently receive inadequate pain medications because of physicians' concern about criminal liability and accusations against them of crossing the line between comfort care and euthanasia. My elderly mother was one such victim, and I am still haunted by her death last year. After a number of admissions over a period of a year during which time her quality of life continued to decline, she had elected to be removed from a ventilator, knowing that she would die. The hospital's ICU physician did not explain to her or me that they were going to insist on a “breathing trial” rather than sedating her with morphine or other drugs before they removed the breathing support. After their trial failed, as expected, they began to titrate morphine intended to “keep her comfortable.” When, after hours of watching her twitch while waiting at her bedside for her to die, I called the doctor in and asked him to increase the morphine as she appeared aware and uncomfortable to me, he refused, saying that he did not want the appearance of having hastened her death. What if someone audited her chart? This, even though mom was 95, had a living will, had granted me medical power of attorney, and had requested being removed from life support and allowed to die in peace. While I would argue that any physician's first duty is to his patient, this physician chose to put himself first and my mother second. His behavior, allowing my mother to experience unnecessary pain for a period of several hours as she lay dying, was despicable and inexcusable... yet sadly still somewhat understandable given the justified fear medical professionals have of being second-guessed by “reviewers” after the fact.

Another pressing concern is health care workers' potential response to future disasters. We are currently faced with the influenza season approaching and the continued concerns about a severe “swine flu” epidemic. I am an Infectious Diseases physician and likely will be working long, hard hours should an influenza epidemic occur. This week, I received an e-mail from my state's medical association asking me to register as a volunteer in case of a bioterrorism or natural disaster emergency. I reflexively signed up. After all, I was raised to help others, and chose to enter a “helping' profession. Now, reminded of the persecution of this fine physician and two nurses, I feel ambivalent.

Dr. Daniel Sokol discussed the ethics of healthcare workers “duty of care” in responding to virulent epidemics. While no clear conclusion can be made, I appreciate Dr. Sokol’s discussing the multiple roles that physicians have that may be in conflict. For while a doctor has an obligation to patients, they also have:
“a duty to care for their own children by protecting them (and hence themselves) from infection. So a further problem with the duty to care, aside from its vagueness, is that it fails to consider the holder of the duty as a multiple agent belonging to a broader community. Doctors and other medical professionals, in such situations, play several incompatible roles—health care worker, spouse, parent, for example—and they must deal with them as best they can. The limits of the duty of care are thus also defined by the strengths of competing "rights and duties.”

Add to that burden of responsibility the possibility of criminal prosecution for triaging patients and allocating the scarce resources that are likely to be available, be it medication or access to ventilators and ICU care, and you can anticipate the most likely outcome.

The irresponsible charges brought against Dr. Pou and her colleagues will have a chilling effect on other health care workers in the future, who will be loathe to respond to disasters. First, there is the risk of malpractice for caring for patients outside our specialties or beyond our experience. Now there is the risk of the destruction of one's reputation and career, not to mention crippling legal defense bills and even prison from attacks from Monday morning quarterbacks.

Enough of the attacks from the protection of the sidelines. Their attackers are, in effect, tying to impose 21st Century legal, moral and ethical obligations on a staff that was forced to operate for several days under 16th Century conditions. Dr. Pou and her nurse colleagues should be hailed for their heroism and devotion to their patients.

Given the conditions that are likely to exist during the next emergency, be it a natural disaster, an epidemic or an attack – limited or no power, lack of equipment and supplies, shortage of staff and no relief staff – would you want to stay and help? Who will be willing to risk his or her career and incur thousands upon thousands of dollars in legal fees defending herself? Who will care for you during the next disaster or epidemic?

Let us put this entire story into perspective by recalling that the true guilty parties in the Katrina debacle were the incompetent and irresponsible officials—most notably Bush and his “Heck-of-a-job, Brownie” FEMA head who failed to protect New Orleans and then further betrayed it's citizens with falsehoods – and not the healthcare workers who devotedly stayed and provided the best care they could under almost unimaginable conditions.

Comparative Effectiveness Research-Rational Healthcare or Healthcare Rationing?

I've been reading about the comparative effectiveness research debate and found my understated quote of the week in the normally staid New England Journal: "Developers face few incentives to conduct active-comparator superiority trials and understand that they benefit from the unacknowledged deficiency of evidence. The development or marketing of me-too drugs and devices may provide a greater return on investment than research aimed at true clinical innovation."

For those who might not have been able to keep up, the focus on comparative effectiveness became more urgent, given soaring healthcare costs, enormous budget deficits, and the strained economy.

While traditional trials usually centered on establishing the efficacy of a drug or device compared to a placebo (a non-inferiority trial), the new focus is on comparing the effectiveness between available therapies. This research is a congressional mandate as part of the American Recovery and Reinvestment Act (ARRA) of 2009. The law provided that the Institute of Medicine (IOM) should make recommendations for national priorities for CER funding—which they did in remarkably short time.

Not surprisingly, the CER plan has come under attack by pharmaceutical companies, despite the assurance, for now, that the research will not be used to restrict physician prescribing choices based on cost-effectiveness data. Others are concerned that, rather than supporting rational healthcare decision-making, the CER initiative is the first step down the slippery slope towards healthcare rationing. An interesting proposal—intended to close the evidence gap and more directly benefit prescribers and consumers—is to have the FDA require comparative effectiveness labeling on their products, to make the benefits and risks of each product clearly evident.

While the two sides are not evenly matched, making the likely outcome predictable, barring an upset, it will be interesting to watch this debate evolve.

Genzyme's Business Model-You've Got to Read This!

An excellent, thought provoking article by Stephen Heuser, "One girl's hope, a nation's dilemma," appeared in the Boston Globe on June 14. Mr. Heuser details the appalling, rapacious approach Genzyme takes to marketing orphan drugs. A guest response, detailing some of the lesser known implications of Genzyme's predatory practices, follows:

"The Boston Globe article about Genzyme’s business tactics is quite alarming.
Nearly every country in Latin America has incorporat ed a legal guarantee to the "right to the highest attainable standard of health" (a.k.a. right to health) in their constitutions. This judicial language has been enforced in a number of countries.

The right to essential medicines is defined by WHO as “those that satisfy the priority health care needs of the population," with the caveat that they “are intended to be available within the context of functioning health systems at all times in adequate amounts, in the appropriate dosage forms, with assured quality, and at a price the individual and the community can afford."

Recent court cases, particularly in Brazil (initially surrounding access to ARVs) have increasing granted the right to access to essential medicines in Latin America, insisting that the government provide the drugs, no matter the cost. In the past this has led to successful cost-lowering mechanisms which both made the drugs available and didn't run the health budget completely dry. For instance, Brazil put significant pressure on international pharmaceutical companies to lower the prices on anti-retrovirals by developing the pharmaceutical capacity to produce their own generic forms as well as fighting heavily in the World Trade Organization. They also focused attention on prevention efforts, as a way to curb the number of people who would eventually need the drugs.

However, the same leverage does not necessarily apply to a small country like Costa Rica. The pharmaceutical capacity is probably not there, and it is too small a population for market interest in many circumstances.

But this particualar case raises a interesting and less discussed issue--- are drugs for rare diseases considered essential medicines, and does the government have the responsibility to provide them to any affected citizens, no matter the cost? In some ways the problem is ultimately about the ability of the pharmaceutical country to charge any amount, unrelated to a reasonable assessment of the costs of production and a marginal profit.

The U.S. has dealt with the issue of rare diseases by creating special incentives for companies to develop drugs for these diseases, on the assumption that there will be no market for profits. This has been moderately successful.

But Genzyme, is breaking the rules (at least in a moral sense). They are using very dirty tactics and enormous resources to engage governments in a questionable manner. While the right to health is open to interpretation, I find it hard to justify such enormous expenditures for so few individuals. That being said, it is not inconceivable for the drug to be viewed as essential.

The problem really lies in the fact that the company is charging such an enormous price, with a huge profit margin, and very little threat of competition in the form of generics, and they stay below the public health activists radar to a great degree.

While pharmaceutical companies have the right to make a profit, just like any other corporation, they should not be allowed to intentionally drain the already strapped resources of the Ministries of Health of developing countries."

Heather Stone
Founder, President of G.A.A.P.E.:
Global Action Against Poverty Everywhere!
Smith College

International Clinical Trials Day

Tomorrow, May 20, is International Clinical Trials Day.

This annual event was established by the European Clinical Research Infrastructures Network, a group formed to help interconnect national networks of clinical research centers across the European Union and to help streamline multi-national studies.

ECRIN launched the International Clinical Trials Day in 2005 to educate the public about clinical trials and to further discussion amongst various interested parties, including clinicians, industry sponsors, ethics committees, regulatory agencies, and patients.

May 20th was selected as the appropriate date for this celebration in honor of James Lind who in 1747 conducted a six-way comparison of cider, elixir of vitriol, vinegar, sea water, oranges and lemons, and a purgative mixture of spices, garlic and mustard seeds on sailors suffering from scurvy. Each treatment group had 2 men. Within 6 days, the two men receiving citrus fruits were well--such a dramatic improvement compared to the other groups that it made the statistical analysis unnecessary. His descriptive treatise was published in 1753 and makes for interesting reading.

When less than 5% of patients with cancer participate in clinical trials, it is clear that a bit more outreach still needs to be done, to educate physicians and patients—and insurance companies, who often have archaic rules that preclude participation. The Public Library of Science (PLOS) is trying to do its part and launched its open access clinical trials journal, also on May 20th.

Some other efforts are not quite as supportive. It probably doesn’t help when a mascot is proposed, “Clint,” the clinical trials guinea pig …nor when a celebration includes discussion of heart-warming topics like “inspections.”

What would you suggest as an enticing celebratory event? How do you encourage participation in, and support of clinical trials?

AccessCR-a Great Source of Infomation

A few months ago I discovered AccessCR, an Australian company with expertise in clinical research. Janelle Bowden, PhD, AccessCR's Managing Director, has a wealth of experience in clinical research and an obvious passion for making research accessible to and more accepted by the public. She also aims to improve communication and partnership between all involved in the clinical research process, from patient to researcher to government to industry. Her website and newsletter reflect that and are a terrific source of frequently updated information.

I’ve been following Dr. Bowden’s site avidly for several months and recently had the pleasure of speaking with her about some of the problems confronting clinical trials both in the US and abroad. I look forward to exploring this with her more in the future.

I highly recommend the AccessCR site and newsletter for interesting updates on clinical trials. Check it out here!

A Virtual Personal Assistant for Researchers and Writers

In my never ending quest to be more organized and keep track of little snippets of information that might be useful, well…sometime…I came across a couple of helpful tools worthy of sharing.

First is Zotero. Great application, and easy enough even for determinedly non-techie types to learn. I was attracted to try Zotero by its pedigree—the project is produced by Center for History and New Media at George Mason University, and is funded by the Andrew W. Mellon Foundation, the Institute of Museum and Library Services, and the Alfred P. Sloan Foundation. They provide Zotero as a free program, which is installed onto Firefox. When you see a page you want to save while you are browsing, you can hit the friendly little Z icon. A screen will pop-up in the lower part of your open Firefox page, and you can take a snapshot of the page or just save the link. There are a number of very easy to follow screencast tutorials that illustrate different aspects of saving or searching, but much of Zotero is self-explanatory.

For me (and other OCD researchers, I suspect), one of the best parts of the Zotero program is that it automatically captures citation information from the web pages or papers. This tool is invaluable and would have saved me countless hours and angst when I was trying to verify all of my references for my book, Conducting Clinical Research, just prior to going to press.

Other great features of Zotero are that:
-You can save pretty much any type of article or file—newspaper clippings, images, pdfs, web pages, and word files. You can then link these to files or pdfs and tag them. Zotero’s search feature has jogged my memory accurately, thus far. I don’t know if that will change as I add a zillion more references, or if the program will choke; I suspect it is tougher than I am.

-You can make linked or standalone notes. I like to jot down “factoids” but sometimes have trouble remembering which articles they were associated with. Now I can more easily link the two together in an easily searchable database.

-You can readily mark up or annotate your pdfs for later reference.

-Rumor has it that you can integrate Zotero with word processing programs. I haven’t tried yet. Nor have I tried accessing my files in cyberspace.

-You can also work with Zotero off-line.

-Zotero is open-source, a goal worthy of support.

What’s not to like? Not much, so far.

-I don’t like the way it identifies folders, as you can’t tell what is in them readily.
-When it takes a snapshot of a page, I wish it would discard a lot of the images or advertising on a web page and save space, but it hasn’t learned that skill yet. Zotero stored my files in a peculiar path, which made backing up my files like a scavenger hunt at first.

I’m sure there are other features I’ll learn to love. If a little elf came with Zotero and would go back through all the other folders on my hard drive’s files and import them into Zotero, along with suitable tags, I would commit to Zotero for life.

Zotero is a great little program that should save considerable time and angst by helping to collect, manage, and accurately cite references in writing any type of article. It really is almost like having a personal research assistant, only a lot less expensive. Let me know what you think!

Comic Relief from Swine Flu

Funny Swine flu song from Putnam Pig! Welcome relief. . .but time to go back to work updating the Medpedia site. Care to join me in that task? Medpedia is an exciting new project, but the wiki will work better with input and discussion from others. Come and join the fun.

Swine Flu on Medpedia

After a hiatus from writing while working and traveling, I’m settling back in, prompted by the H1N1 (swine) flu outbreak. I’m honored to have been asked to work with Medpedia on providing information on this topic. I adapted some from CDC, WHO, CIDRAP, and others. Please check the Medpedia.com/Influenza A H1N1 site, which I will update regularly, trying to provide news and perspective on recommendations in a common sense way. Other physicians will also hopefully contribute to this great new medical wiki project. Please also e-mail me with questions you would like answered or leave a comment. Thanks!

FDA Approves a New Drug for the Annoyingly Cheerful

In one of the best satires I've seen since "That Was the Week That Was," the Women's Bioethics Blog called my attention to the FDA's approval of Pfizer's new drug, Despondex, to cure the Pollyannas among us.



I wonder how sales will compare to Viagra? Stay tuned...

Medpedia-A Valuable Health Wiki is Born

Eye on FDA, one of my favorite sources, brought Medpedia's launch to my attention today. Medpedia is a authoritative medical wiki powered by a collaboration between the medical schools of Harvard, Stanford, Michigan, and the University of California Berkely School of Public Health.

As a wiki, Medpedia will likely be fluid, uptodate, and interactive. It promises to provide a wealth of useful information about health and medically related topics. Check it out!

Farewell to Pharmalot...and Ed Silverman's Return

I was delighted to discover that Ed Silverman, of Pharmalot fame, will be blogging again. He can now be found occasionally on the InVivo blog.

It was nice, albeit sad, to see his farewell from Pharmalot.



While I wish I had discovered his blog earlier, I enjoyed reading it very much--his writing was often pointed, provocative, and perceptive...and always thought-provoking.

I wish Ed the best, and hope we'll hear from him regularly from his new home.

Algeferin Conquers Antibiotic Resistant Bacteria: Too Good to be True?

An intriguing report from Science News touts the discovery of algeferin, a chemical from sponges. Algerferin said to be able to reprogram antibiotic resistant bacteria to make them susceptible to antibiotics again. Preliminary tests against "superbugs" (such as MRSA) and biofilms are said to be very promising.

The potential for treating biofilms, clusters of bacteria that cause serious nosocomial (hospital acquired) infections by adhering to foreign devices, such as IV catheters, is quite intriguing, as such infections are particularly difficult to treat. Especially notable was the statement that biofilms "dissolved when treated with fragments of the algeferin molecule. And new biofilms did not form."

Thus far, algeferin has been tested against a variety of resistant organisms, including MRSA and Pseudomonas. That the chemical can restore bacterial susceptibility to antibiotics would be terrific, if it holds up. We are running out of effective antibiotics, which are often irresponsibly squandered (from bacterial resistance partly due to inappropriate use of these drugs for viral illness and in “animal growth” feed, for example). Resistant bacteria are also spread throughout hospitals and nursing homes by ineffective or sometimes irrational infection control policies, as well as by carelessness and increasingly harried staff.

The promise of algeferin is quite exciting...but based on the history of antibiotic development, misuse, and resistance, I have little doubt the bacteria will outsmart algeferin--or its prescribers-- too.

Nigerian Suit Against Pfizer Revived in U.S.

There is more to the Nigerian Trovan trial debate than has been mentioned in the Washington Post and similar articles. First, it is important to note that some illnesses are more common in developing countries—e.g., the “meningitis belt” in Africa, and thus studies need to be conducted in these settings, rather than in the U.S.

For example, in the 1996 meningococcal meningitis outbreak in Nigeria, ~12,000 children died over 6 months. (Three or four cases in a U.S. community would be considered an “outbreak.”) Pfizer’s study compared Ceftriaxone, given by intramuscular injections, to Trovafloxacin, given orally. Pfizer has been criticized regarding their informed consent documentation and IRB approval–not without justification, from the second-hand reports I’ve read, but…

What is rarely mentioned is that the survival rate was reportedly 94.4% Trovan vs. 93.8 Ceftriaxone. Nor is it widely known that Trovan was also being studied for meningitis in the US by well-respected pediatric infectious diseases specialists. The outcome in the US was clinical success in 79% of the Trovan patients vs. 81% in the Ceftriaxone group, and the longer-term sequelae showed no difference between the groups. (The Pediatric Infectious Disease Journal:Volume 21(1) January 2002, pp 14-22)

Nor is the value of developing oral treatments for infections generally discussed. Doctors Without Borders was treating other meningitis with intramuscular injections of Chloramphenicol—a wonderful drug that is now rarely used because it kills ~1/30,000 patients who receive it.

Multiple IM injections are painful, require sterile technique and more skilled health care workers than do oral medications. Supplies for injected drugs are more difficult and expensive to handle and administer, particularly in poorer, tropical countries.

Pfizer may not have not conducted this trial perfectly or with adequate informed consent—I don’t know, as I wasn’t there. But I do know the horror of watching young people die from meningococcal disease, and I do understand the rationale and goal of developing an oral drug for a devastating disease that episodically kills thousands of children. While I am often critical of this company, they deserve a fair trial.

Politics, One: Women, Zero

Last week, I was very buoyed by President Obama’s eloquent speeches and talk of rising above politics, particularly with his repealing the Global Gag rule. Today, I am sorely disappointed by Obama’s selling out to Republican conservatives, removing a provision in the proposed Economic Stimulus package that would have provided family planning coverage through Medicaid to more low-income women. This pandering to the right is at the expense of women’s health care needs and economic well-being.

The Religious Coalition for Reproductive Choice's president, Rev. Carlton Veazey, notes that a woman living in poverty is four times as likely to have an unintended pregnancy and five times as likely to have an unintended birth as a higher-income counterpart. Allowing more access to family planning services and contraceptives enables a woman to better choose when and how many children she might be able to support and nurture, and allows her to time pregnancies to enable her to become more educated or further advance herself. Denying these services is perpetuating the old efforts to keep the women barefoot and pregnant—and is in stark contrast to what is in the best interests of the women. Nor does it illustrate the promise of rational, evidence based decision-making.

The decision to cut family planning is short-sighted in other ways, too. Economically, a 2007 Congressional Budget Office report estimated that this Medicaid provision would save the government $200 million over five years by decreasing costs related to pregnancies and post-natal care.

Additionally, didn’t Obama say his goal was to reduce unwanted pregnancies and the need for abortions? This is an odd way of going about it.

With the tanking economy and sky-rocketing unemployment, women are facing loss of jobs, healthcare, or their housing. They should not have the added burden of facing unintended pregnancies through misogynist policies.

It is ironic that women’s needs got short shrift in an obvious attempt to curry favor and win Republican support for the economic package—even though those votes were not necessary for passage. How successful was this strategy? It garnered zero votes.

So, once again, the score is Politics, One: Women, Zero.

A Refreshing News Model-Rachel Maddow

I don’t watch much TV…but while surfing around before the election, I stumbled upon the Rachel Maddow show, and was immediately enthralled. I have continued to watch her show regularly and remain quite impressed. While the presentation is, on occasion, a bit too light for my taste, I love her wry and perceptive take on the news. This past week had two outstanding shows you can view via podcasts, or by getting transcripts.

First, there was Mon 12/15’s clips on the NSA’s warrantless wiretapping and the first interview granted by whistleblower Thomas Tamm. Her subsequent commentary on Bush’s reign was insightful and right-on target. She continued the week with commentaries on absurd aspects of the financial bailouts, environmental and foreign policies, among others. Monday’s show brought us a scathing analysis of the application and oversight of the $700 billion TARP loans, the double standards in access to financial help, and the lack of transparency:

“That‘s it actually. That‘s the whole two pages. That is the full application process for a piece of the $700 billion worth of our money that the government is doling out.

Have you ever applied for a loan for anything? House, car, small business, anything? Have you ever applied for public assistance, unemployment, food stamps welfare? If you haven‘t, I can tell you this, the application asks for more of a commitment than name, address, how much do you want, anything else we should know, love, Bilbo Baggins.

For regular humans—that‘s not what getting a loan is like. It‘s certainly not what getting welfare is like, which is why I‘m going to try to turn myself into a bank holding company. Then maybe we all should.”

The final event prompting this post was her frank admission and obvious remorse on Monday, when she confessed to having made an error in making a background check on her guest, economist Laura Tyson. When David Sirota called her attention to an overlooked conflict-of-interest that might well have tainted Tyson’s comments, Dr. Maddow promptly issued an apology, castigating herself in the process.

I had been immediately impressed by Rachel Maddow’s credentials—she is certainly no bimbo, unlike many of the young “reporters” who uncritically read scripts on some of the major news streams. Her bio notes that she holds a degree in public policy from Stanford University. At graduation she was awarded the John Gardner Public Service and Leadership Development Fellowship. She was then awarded a Rhodes Scholarship in 1995, and used it to study at Oxford University, where she received her doctorate. She has a long-standing passion for social justice issues, having previously focused on prison reform, HIV/AIDS, and Health Care Reform.

It has been a joy to watch a bright, highly-educated young woman anchoring a prominent show. This week’s candid admission of error greatly raised my esteem for Dr. Maddow, as it reflected an unusual level of integrity and humility. Rachel has earned a loyal follower here.